Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tyrosine phosphorylation plays a central role in intracellular signaling by many hormones and growth factors. Termination of the signal is thought to involve dephosphorylation of target proteins by phosphotyrosine phosphatases (PTPase). Soluble protein PTPases from neonatal rat osteoblasts (ROBs) and rat osteosarcoma (ROS 17/2.8) cells were chromatographically distinguished and characterized using 32P-labelled glutamate/tyrosine co-polymer as substrate. Two activities from both cell types were chromatographically separable. The dominant PTPase activity in the presence of 60-125 mM salt (E1), was eluted from phosphocellulose by 180-280 mM NaCl, bound weakly to a strong anion exchange column (QAE-trisacryl), had an apparent Km for [32P]glutamate/tyrosine copolymer of 52 micrograms/ml, was enhanced (5-10-fold, ROS; 1.5-3-fold, ROB) by assay in 125 mM NaCl, had no significant alkaline, acid, or serine phosphatase activity and had an M(r) of 53,000. A second activity (E2) was not retained by phosphocellulose but eluted from QAE-trisacryl in a single peak at 90-130 mM NaCl. It had an apparent Km for [32P]glutamate/tyrosine copolymer of 30 micrograms/ml (ROS) and its activity was not enhanced by NaCl in the assay. Activity E1 from both cells was 50% inhibited by 0.05 microM Na3VO4, 20 microM ZnCl2, or 5-10 microM CoCl2, but not by 1 mM NaF; activity E2 had a similar inhibition profile, but was more sensitive to ZnCl2 (IC50, 5 microM). Co2+ is a relatively non-toxic metal which may be a useful tool for investigating the role of phosphotyrosine in osteoblast proliferation and function. The similarity between the E1 activity from ROS cells and ROBs suggests that ROS cells may be useful in studying PTPase regulation by hormones, but molecular approaches will be required to establish the identity of PTPases in ROBs and ROS cells.
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PMID:Rat osteoblasts and ROS 17/2.8 cells contain a similar protein tyrosine phosphatase. 790 81

Rho, a member of the small GTP-binding proteins, and one of its downstream effectors ROCK (Rho-associated coiled-coil forming protein kinase) play an important role in the invasion of tumor cells. Lysophosphatidic acid (LPA) activates Rho and ROCK and promotes the organization of stress fibers and focal adhesions. However, the effect of LPA on tumor cell invasion is still controversial. In the present study, human osteosarcoma cells treated with a high concentration of LPA (high LPA) showed considerable formation of stress fibers and focal adhesions compared to the cells treated with a low concentration of LPA (low LPA). C3 (inhibitor of Rho) or Y27632 (an inhibitor of ROCK) inhibited the effects of LPA, indicating that LPA activates the Rho-ROCK pathway in the cells. In addition, Rho activation assay showed that the activation level of Rho can be altered by changing the concentration of LPA. Low LPA stimulated the motility and invasion of the cells, while high LPA reduced both. The disruption of extracellular matrix (ECM) by matrix metalloproteinase 2 (MMP2) is also critical for tumor cell invasion. MMP2 is activated by membranous type-1 MMP (MT1-MMP) and type-2 tissue inhibitor of MMP (TIMP2). High LPA suppressed the activation of MMP2 through down-regulation of MT1-MMP and TIMP2. C3 and Y27632 reversed the suppression of the activation of MMP2 and expression of MT1-MMP and TIMP2, suggesting the involvement of the Rho-ROCK pathway in ECM degradation. Tyrosine phosphorylation of focal adhesion kinase (FAK) was also required for the invasion of tumor cells to occur. Low LPA enhanced the tyrosine phosphorylation of FAK whereas high LPA reduced it. In conclusion, we suggest that Rho has a dual effect on the invasion of osteosarcoma cells by modulating the motility, the ability to degrade ECM and tyrosine phosphorylation of FAK.
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PMID:Small GTP-binding protein, Rho, both increased and decreased cellular motility, activation of matrix metalloproteinase 2 and invasion of human osteosarcoma cells. 1134 66

To acquire information on signal alteration corresponding to the changes in metastatic potential, we analysed protein tyrosine phosphorylation of low- and high-metastatic human osteosarcoma HuO9 sublines, which were recently established as the first metastatic model of human osteosarcoma. Tyrosine phosphorylation of proteins around 60, 70, and 120-130 kDa was enhanced in high-metastatic sublines. Among these proteins, the protein around 70 kDa, which was most remarkably phosphorylated, was identified as paxillin, a scaffold protein in integrin signaling. Activity of Src family kinase correlated well with metastatic potential, and a Src family kinase inhibitor, PP2, not only abolished tyrosine phosphorylation of paxillin but also impaired the motility of high-metastatic sublines. The expression of paxillin was also elevated in high-metastatic sublines, and knocking down of paxillin expression by RNAi method resulted in attenuated motility of high-metastatic cells. We also demonstrated that the phosphorylated form of paxillin is essential for the migration-promoting effect in human osteosarcoma. These findings suggest that enhanced activity of Src family kinases and overexpression of paxillin synergistically contribute to the high metastatic potential of human osteosarcoma through the hyperphosphorylation of paxillin.
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PMID:Tyrosine phosphorylation of paxillin affects the metastatic potential of human osteosarcoma. 1587 Jun 99

Tyrosine-kinase inhibitor (TKI) therapy for human cancers is not curative, and relapse occurs owing to the continued presence of tumor cells, referred to as minimal residual disease (MRD). The survival of MRD stem or progenitor cells in the absence of oncogenic kinase signaling, a phenomenon referred to as intrinsic resistance, depends on diverse growth factors. Here we report that oncogenic kinase and growth-factor signaling converge to induce the expression of the signaling proteins FBJ osteosarcoma oncogene (c-FOS, encoded by Fos) and dual-specificity phosphatase 1 (DUSP1). Genetic deletion of Fos and Dusp1 suppressed tumor growth in a BCR-ABL fusion protein kinase-induced mouse model of chronic myeloid leukemia (CML). Pharmacological inhibition of c-FOS, DUSP1 and BCR-ABL eradicated MRD in multiple in vivo models, as well as in mice xenotransplanted with patient-derived primary CML cells. Growth-factor signaling also conferred TKI resistance and induced FOS and DUSP1 expression in tumor cells modeling other types of kinase-driven leukemias. Our data demonstrate that c-FOS and DUSP1 expression levels determine the threshold of TKI efficacy, such that growth-factor-induced expression of c-FOS and DUSP1 confers intrinsic resistance to TKI therapy in a wide-ranging set of leukemias, and might represent a unifying Achilles' heel of kinase-driven cancers.
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PMID:Targeting c-FOS and DUSP1 abrogates intrinsic resistance to tyrosine-kinase inhibitor therapy in BCR-ABL-induced leukemia. 2831 94